1. Field
The invention is related to nikkomycin derivatives, antimycotic compositions containing nikkomycin derivatives, antimycotic compositions comprising fungicidally effective amounts of a nikkomycin derivative and an azole antimycotic, the preparation of such compositions and the methods of treating infections of fungi by administering therapeutically effective amounts of such compositions.
2. Prior Art
Compounds inhibitory to the synthesis of fungal cell wall material (synthase inhibitors) have been reported recently to have demonstrable effects against fungi of agricultural importance (U.S. Pat. Nos. 4,315,922 and 4,158,608; see also U.S. Pat. Nos. 4,585,761 and 4,552,954 for descriptions of the preparation and purification of such compounds). The agents mentioned in the cited patents, nikkomycins, together with similar agents known as polyoxins, are known to act by interfering with the synthesis of chitin in the cell walls of fungi. Because fungi of medical importance to humans also have varying amounts of chitin in their cell walls, experiments have been conducted to determine if the chitin synthase inhibitors are capable of inhibiting the growth of such fungi (Hector and Pappagianis, J. Bacteriol. 154:488-498, 1983, and Hector and Braun, Antimicrobial Agents Chemother, 29:389-394, (1986). In earlier work, certain fungi such as Candida albicans were reported to be insensitive to chitin synthase inhibitors (see Naider et al, Antimicrobial Agents Chemother, 24:787 796, 1983). Subsequently, C. albicans was found to be more sensitive to nikkomycins than polyoxins (see Yadan et al, J. Bacteriol. 160:884-888, 1984).
Quite surprisingly, it was now found that nikkomycin derivatives in combination with antimycotically active azoles are efficacious in treating fungal infections in human and non-human animals, especially by parenteral but also oral application and administration.
As shown in synergy studies the achieved antifungal effect is also a synergistic effect based on combining the nikkomycin derivatives with antimycotic azoles.
Accordingly, the invention is related to new nikkomycin derivatives and antimycotic compositions comprising a fungicidally effective amount of a nikkomycin derivative and an azole antimycotic.
The nikkomycin derivatives of the invention are represented by the general formulae (N) ##STR1## wherein R.sub.n represents ##STR2## a) R.sub.w denotes H or --CH.sub.2 --X, wherein X is H, alkyl, preferably C.sub.1 -C.sub.6 -alkyl, aryl, preferably C.sub.6 -C.sub.18 -aryl, aralkyl, preferably C.sub.6 -C.sub.12 -aryl-C.sub.1 -C.sub.6 -alkyl or any other saturated or unsaturated organic radical and R.sub.y denotes --Ch.sub.2 --X, wherein X has the aforementioned meaning;
b) R.sub.w denotes H and R.sub.y denotes ##STR3## wherein X' is any saturated or unsaturated organic radical, especially a radical derived from a natural amino acid; PA0 c) R.sub.w denotes H and R.sub.y denotes a radical ##STR4## wherein X has the meaning mentioned under a) and b) hereinbefore and wherein X' has the meaning of the natural amino acids Gly, Val, Leu, Ile, Ser, Asp, Asn, Glu, His, Gys, Met and Phe or ##STR5## d) R.sub.w denotes H and R.sub.y has the meaning of ##STR6## wherein a') R.sub.n' denotes H or --CH.sub.2 --X and R.sub.v' denotes --CH.sub.2 --X, wherein X has the meaning mentioned under a) hereinabove; PA0 b) R.sub.w denotes H and R.sub.y denotes ##STR11## wherein X' is any saturated or unsaturated organic radical, especially a radical derived from a natural amino acid; PA0 c) R.sub.w denotes H and R.sub.y denotes a radical ##STR12## wherein X and X' have the meaning mentioned under a) and b) hereinbefore with the proviso that X' has not the meaning ##STR13## d) R.sub.w denotes H and R.sub.y has the meaning of ##STR14## wherein a') R.sub.n' denotes H or --CH.sub.2 --X and R.sub.v' denotes --CH.sub.2 --X, wherein X has the meaning mentioned under a) hereinabove; PA0 b) R.sub.w denotes H and R.sub.y denotes ##STR19## wherein X' is any saturated or unsaturated organic radical, especially a radical derived from a natural amino acid; PA0 c) R.sub.w denotes H and R.sub.y denotes a radical ##STR20## wherein X and X' have the meaning mentioned under a) and b) hereinbefore; d) R.sub.w denotes H and R.sub.y has the meaning of ##STR21## wherein a') R.sub.n' and R.sub.v' denote H; PA0 B represents a nitrogen atom or the CH group, PA0 X represents a hydrogen or alkyl, PA0 Y represents alkyl, or alkenyl, alkinyl or optionally substituted benzyl, if X represents hydrogen, and PA0 R represents optionally substituted phenyl or the grouping ##STR26## wherein Alk.sup.1 represents alkyl and PA0 Alk.sup.2 represents straight-chain or branched alkyl, or PA0 Alk.sup.1 and Alk.sup.2 together represent a cycloaliphatic ring, PA0 X represents a nitrogen atom or the CH group, PA0 Y represents a nitrogen atom or the CH group and PA0 R represents in each case optionally substituted phenyl, phenylalkyl, phenoxy, phenylthio, phenoxyalkyl, phenylthioalkyl, benzyloxy or benzylthio, PA0 Alk.sup.1 represents straight-chain or branched alkyl with 1 to 4 carbon atoms; and PA0 Alk.sup.2 represents straight-chain or branched alkyl with 1 to 4 carbon atoms; or PA0 Alk.sup.1 and Alk.sup.2 together represent a 3-membered to 7-membered cycloaliphatic ring, PA0 X represents a nitrogen atom or the CH group; PA0 Y represents a nitrogen atom or the CH group; and R represents phenyl, phenylalkyl with 1 to 4 carbon atoms in the alkyl part, phenoxy, phenylthio, phenoxyalkyl with 1 to 4 carbon atoms in the alkyl part, phenylthioalkyl with 1 to 4 carbon atoms in the alkyl part, benzyloxy or benzylthio, each of which is optionally mono-, di- or tri-substituted in the phenyl part by identical or different substituents, preferred substituents which may be mentioned being: halogen, alkyl with 1 to 4 carbon atoms, alkoxy and alkylthio with in each case 1 to 4 carbon atoms, halogenoalkyl, halogenoalkoxy and halogenoalkylthio with in each case 1 or 2 carbon atoms and 1 to 5 identical or different halogen atoms, such as, preferably, fluorine and chlorine atoms, nitro, cyano, hydroxyl, hydroxycarbonyl, alkoxycarbonyl with 1 to 4 carbon atoms in the alkyl part, alkoximinoalkyl with 1 to 4 carbon atoms in each alkyl part, and phenyl, phenoxy, benzyl and benzyloxy, each of which is optionally substituted by halogen and/or alkyl with 1 or 2 carbon atoms. PA0 Alk.sup.1 represents methyl or ethyl; and PA0 Alk.sup.2 represents methyl or ethyl; or PA0 Alk.sup.1 and Alk.sup.2, together with the carbon atom to which they are bonded, represent cyclobutyl, cyclopentyl or cyclohexyl, PA0 X represents a nitrogen atom or the CH group; PA0 Y represents a nitrogen atom or the CH group; and PA0 R represents phenyl, benzyl, phenethyl, phenoxy, phenylthio, phenoxymethyl, phenoxyethyl, phenylthiomethyl, phenylthioethyl, benzyloxy or benzylthio, each of which is optionally mono- or disubstituted in the phenyl part by identical or different substituents, substituents which may be mentioned being: fluorine, chlorine, bromine, methyl, isopropyl, tert.-butyl, methoxy, methylthio, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, nitro, cyano, hydroxyl, hydroxycarbonyl, methoxycarbonyl, ethoxycarbonyl, hydroximinoethyl, 1-hydroximinoethyl, methoximinomethyl, 1-methoximinoethyl, and phenyl, phenoxy, benzyl and benzyloxy, each of which is optionally substituted by fluorine, chlorine or methyl. PA0 R represents hydrogen, alkyl, alkenyl, alkinyl, trialkylsilyl, optionally substituted phenylalkyl or the acyl radical, PA0 X represents a nitrogen atom or the CH group, and PA0 Y represents a nitrogen atom or the CH group, PA0 Ar preferably represents phenyl which optionally has one or several, identical or different, substituents, the substituents which may be mentioned as being preferred being: halogen; alkyl, alkoxy and alkylthio each having 1 to 4 carbon atoms; halogenoalkyl, halogenoalkoxy and halogenoalkylthio each having 1 to 2 carbon atoms and 1 to 5 identical or different halogen atoms, such as fluorine and chlorine atoms; as well as phenyl or phenoxy each of which is optionally substituted by alkyl having 1 or 2 carbon atoms and/or halogen; and furthermore represents naphthyl and a 5- to 6-membered heteroaromatic which optionally has one or several identical or different, substituents and nitrogen, oxygen and/or sulphur as the heteroatoms, the suitable substituents which are preferred being the abovementioned phenyl substituents; PA0 R preferably represents hydrogen, straight-chain or branched alkyl having 1 to 4 carbon atoms, straight-chain or branched alkenyl and alkinyl each having 2 to 4 carbon atoms, trialkylsilyl having 1 to 4 carbon atoms in each alkyl moiety, alkylcarbonyl having 1 to 4 carbon atoms in the alkyl moiety, and represents phenylalkyl which optionally has one or several, identical or different, substituents, with 1 to 2 carbon atoms in the alkyl moiety, the suitable substituents which are preferring being the phenyl substituents already mentioned for Ar; and PA0 X and Y represent the meanings given in the definition of the invention. PA0 Ar represents phenyl which optionally has one to three, in particular one or two, identical or different substituents, the substituents which may be mentioned being: fluorine, chlorine, methyl, isopropyl, tert.-butyl, methoxy, methylthio, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, and phenyl or phenoxy each of which is optionally substituted by fluorine, chlorine and/or methyl; furthermore represents naphthyl and represents furyl, thienyl, pyridinyl or pyrimidinyl, each of which optionally has one or two, identical or different, substituents suitable substituents being the abovementioned phenyl substituents; PA0 R.sup.1 represents hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, allyl, propargyl, trimethylsilyl, methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, isobutylcarbonyl, and represents benzyl which optionally has one to three, in particular one or two, identical or different substituents, suitable substituents which are preferred being the phenyl substituents already mentioned for Ar; and PA0 X and Y represent the meanings given in the definition of the invention. PA0 R.sup.1 represents hydrogen, alkyl, alkenyl, alkinyl, trialkylsilyl, optionally substituted phenylalkyl or the acyl radical, PA0 R.sup.2 represents halogen, cyano, thiocyano, alkylcarbonyloxy, alkylcarbonylthio or the groups --X--R.sup.3 and --NR.sup.4 R.sup.5, as well as hydrogen when Ar represents optionally substituted heteroaryl, PA0 R.sup.3 represents alkyl, cycloalkyl, alkenyl, alkinyl, hydroxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, optionally substituted aryl, optionally substituted aralkyl, or the radical of the formula ##STR36## R.sup.4 and R.sup.5 are identical or different and represent hydrogen or alkyl and, together with the nitrogen atom to which they are bonded, represent an optionally substituted cycloaliphatic ring which optionally contains other heteroatoms, PA0 X represents oxygen, sulphur, the SO or SO.sub.2 group, and PA0 Y represents a nitrogen atom or the CH group, and their acid addition salts, have good antimycotic properties. PA0 Ar preferably represents phenyl which optionally has one or several, identical or different, substituents, the substituents which may be mentioned as being preferred being: halogen, alkyl, alkoxy and alkylthio each having 1 to 4 carbon atoms; halogenoalkyl, halogenoalkoxy and halogenoalkylthio each having 1 to 2 carbon atoms and 1 to 5 identical or different halogen atoms, such as fluorine and chlorine atoms; as well as phenyl or phenoxy each of which is optionally substituted by alkyl having 1 or 2 carbon atoms and/or halogen; and furthermore represents naphthyl and a 5- to 6-membered heteroaromatic which optionally has one several, identical or different, substituents and nitrogen, oxygen and/or sulphur as the heteroatoms, the suitable substituents which are preferred being the above mentioned phenyl substituents; PA0 R.sup.1 preferably represents hydrogen, straight-chain or branched alkyl having 1 to 4 carbon atoms, straight-chain or branched alkenyl and alkinyl, each having 2 to 4 carbon atoms, trialkylsilyl having 1 to 4 carbon atoms in each alkyl part, alkylcarbonyl having 1 to 4 carbon atoms in the alkyl part, and phenylalkyl which has one or two carbon atoms in the alkyl part and is optionally monosubstituted or polysubstituted by identical or different substituents, preferred substituents being the phenyl substituents already mentioned for Ar, PA0 R.sup.2 preferably represents fluorine, chlorine, bromine, cyano, thiocyano, alkylcarbonyloxy having 1 to 4 carbon atoms in the alkyl part, alkylarbonylthio having 1 to 4 carbon atoms in the alkyl part, or the groupings --X--R.sup.3 and --NR.sup.4 R.sup.5, PA0 R.sup.3 preferably represents straight-chain or branched alkyl having 1 to 18 carbon atoms, cycloalkyl having 3 to 8 carbon atoms, straight-chain or branched alkenyl having 2 to 18 carbon atoms, straight-chain or branched alkinyl having 2 to 18 carbon atoms, hydroxyalkyl having 1 to 18 carbon atoms, alkylthioalkyl having 1 to 6 carbon atoms in the alkylthio part and 1 to 6 carbon atoms in the alkyl part, carboxyalkyl having 1 to 18 carbon atoms in the alkyl part, alkoxycarbonylalkyl having 1 to 6 carbon atoms in the alkoxy part and 1 to 6 carbon atoms in the alkyl part, and phenyl or phenylalkyl having 1 to 2 carbon atoms in the alkyl part, each of which is optionally monosubstituted or polysubstituted by identical or different substituents, preferred substitutents in each case being the phenyl substituents mentioned as being preferred for Ar, or PA0 R.sup.3 represents the radical of the formula ##STR37## R.sup.4 and R.sup.5 independently or one another preferably represent hydrogen or straight-chain or branched alkyl having 1 to 4 carbon atoms, or PA0 R.sup.4 and R.sup.5, together with the nitrogen atom to which they are bonded, preferably represent a 5-membered or 6-membered ring which is optionally substituted by alkyl having 1 to 4 carbon atoms or alkylcarbonyl having 1 to 4 carbon atoms in the alkyl part, and can contain oxygen, sulphur and/or nitrogen as further heteroatoms, and PA0 X preferably represents hydrogen when Ar represents an optionally substituted 5-membered or 6-membered heteroaromatic, and PA0 Y preferably represents nitrogen or a CH group. PA0 Ar represents phenyl which is optionally monosubstituted or trisubstituted, in particular monosubstituted or disubstituted, by identical or different substituents, the following being mentioned as substituents: fluorine, chlorine, methyl, isopropyl, tert.-butyl, methoxy, methylthio, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, and phenyl or phenoxy, each of which is optionally substituted by fluorine, chlorine and/or methyl; and furthermore represents naphthyl, and represents furyl, thienyl, pyridinyl or pyrimidinyl, each of which is optionally monosubstituted or disubstituted by identical or different substituents, suitable substituents being the above mentioned phenyl substituents; PA0 R.sup.2 represents hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, allyl, propargyl, trimethylsilyl, methylcarbonyl, ethylcarbonyl, n-propyl-carbonyl, isopropylcarbonyl, n-butylcarbonyl, isobutylcarbonyl, and benzyl which is optionally monosubstituted or disubstituted, in particular monosubstituted or disubstituted, by identical or different substituents, preferred substituents being the phenyl substituents already mentioned as being preferred for Ar, PA0 R.sup.2 represents fluorine, chlorine, bromine, cyano, thiocyano, methylcarbonyloxy, ethylcarbonyloxy, n-propylcarbonyloxy, isopropylcarbonyloxy, n-butylcarbonyloxy, isobutylcarbonyloxy, methylcarbonylthio, ethylcarbonylthio, n-propylcarbonylthio, isopropylcarbonylthio, n-butylcarbonylthio, isobutylcarbonylthio or the groupings --X--R.sup.3 or --NR.sup.4 R.sup.5, PA0 R.sup.3 represents straight-chain or branched alkyl having 1 to 12 carbon atoms, cycloalkyl having 5 to 7 carbon atoms, straight-chain or branched alkenyl having 2 to 12 carbon atoms, straight-chain or branched alkinyl having 2 to 12 carbon atoms, hydroxyalkyl having 1 to 12 carbon atoms, alkylthioalkyl having 1 to 4 carbon atoms in the alkylthio part and 1 to 4 carbon atoms in the alkyl part; carboxyalkyl having 1 to 12 carbon atoms in the alkyl part, alkoxycarbonylalkyl having 1 to 4 carbon atoms in the alkoxy part and 1 to 4 carbon atoms in the alkyl part, and phenyl or benzyl, each of which is optionally monosubstituted to trisubstituted, in particular monosubstituted to trisubstituted, in particular monosubstituted or disubstituted, by identical or different substituents already mentioned above for Ar as being particularly preferred, or PA0 R.sup.3 represents the radical of the formula ##STR38## R.sup.4 and R.sup.5 independently of one another represent hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl, or PA0 R.sup.4 and R.sup.5 together with the nitrogen atom to which they are bonded, represent piperidinyl, piperazinyl or morpholinyl each of which is optionally substituted by methyl, ethyl, methylcarbonyl or ethylcarbonyl, and PA0 X represents oxygen, sulphur, an SO group or an SO.sub.2 group, and furthermore PA0 R.sup.2 also represents hydrogen when Ar represents one of the above mentioned optionally substituted heteroaromatics, and PA0 Y represents nitrogen or a CH group, PA0 Ar represents optionally substituted aryl, PA0 Y represents a direct bond or the groupings --CH.sub.2 --, --CH.sub.2 --CH.sub.2 --, --OCH.sub.2 --, --SCH.sub.2 --, --CH.dbd.CH-- or --C.tbd.C--, PA0 X represents a nitrogen atom or the CH group, PA0 Z represents oxygen or the NOR.sup.2 group and PA0 R.sup.2 represents hydrogen, alkyl, alkenyl, alkinyl, optionally substituted aralkyl or optionally substituted cycloalkylalkyl,
b') R.sub.n' represents H and R.sub.v' means ##STR7## wherein X' has the meaning mentioned under b) hereinabove; c') R.sub.n' denotes H and R.sub.v' represents ##STR8## wherein X and X' have the meaning given under a) and b) hereinabove or ##STR9## wherein R.sub.n represents ##STR10## a) R.sub.w denotes H or --CH.sub.2 --X, wherein X is H, alkyl, preferably C.sub.1 -C.sub.6 -alkyl, aryl, preferably C.sub.6 -C.sub.18 -aryl, aralkyl, preferably C.sub.6 -C.sub.12 -aryl-C.sub.1 -C.sub.6 -alkyl or any other saturated or unsaturated organic radical and R.sub.y denotes --CH.sub.2 --X, wherein X has the aforementioned meaning; PA1 b') R.sub.n' represents H and R.sub.v' means ##STR15## wherein X' has the meaning mentioned under b) hereinabove; c') R.sub.n' denotes H and R.sub.v' represents ##STR16## wherein X and X' have the meaning given under a) and b) hereinabove or ##STR17## wherein R.sub.n represents ##STR18## a) R.sub.w denotes H or --CH.sub.2 --X, wherein X is H, alkyl, preferably C.sub.1 -C.sub.6 -alkyl, aryl, preferably C.sub.6 -C.sub.18 -aryl, aralkyl, preferably C.sub.6 -C.sub.12 -aryl-C.sub.1 -C.sub.6 -alkyl or any other saturated or unsaturated organic radical and R.sub.y denotes --CH.sub.2 --X, wherein X has the aforementioned meaning; PA1 b') R.sub.n' denotes H or --CH.sub.2 --X and R.sub.v' denotes --CH.sub.2 --X, wherein X has the meaning mentioned under a) hereinabove; PA1 c') R.sub.n' represents H and R.sub.v' means ##STR22## wherein X' has the meaning mentioned under b) hereinabove; d') R.sub.n' denotes H and R.sub.v' represents ##STR23## wherein X and X' have the meaning given under a) and b) hereinabove. If X' is an organic radical than preferably a saturated or unsaturated aliphatic radical, such as C.sub.1 -C.sub.10 -alkyl, alkenyl or alkinyl or a substituted or unsubstituted aromatic radical with 6 to 12 C-atoms or a heterocyclic radical, especially of the group consisting of ##STR24## PA1 Alk.sup.2 represents alkyl, or PA1 Alk.sup.1 and Alk.sup.2 together represent a cycloaliphatic ring, and PA1 R.sup.1 represents alkyl, alkenyl or in each case optionally substituted phenyl, phenylalkyl, phenoxy, phenylthio, phenoxyalkyl, phenylthioalkyl, benzyloxy or benzylthio, PA1 Alk.sup.2 represents straight-chain or branched alkyl with 1 to 4 carbon atoms; or PA1 Alk.sup.1 and Alk.sup.2, together with the carbon atom to which they are bonded, represent a 3-membered to 7-membered cycloaliphatic ring; and PA1 R.sup.1 represents straight-chain or branched alkyl with 1 to 6 carbon atoms, alkenyl with 2 to 4 carbon atoms, or phenyl, phenylalkyl with 1 to 4 carbon atoms in the alkyl part, phenoxy, phenylthio, phenoxyalkyl with 1 to 4 carbon atoms in the alkyl part, phenyl, thioalkyl with 1 to 4 carbon atoms in the alkyl part, benzyloxy or benzylthio, each of which is optionally mono-, di- or tri-substituted in the phenyl part by identical or different substituents, preferred possible substituents being the substituents on phenyl already mentioned for R. PA1 Alk.sup.2 represents methyl or ethyl; or PA1 Alk.sup.1 and Alk.sup.2, together with the carbon atom to which they are bonded, represent cyclobutyl, cyclopentyl or cylohexyl; and PA1 R.sup.1 represents methyl, ethyl, n-propyl, i-propyl, n-butyl, neopentyl, or phenyl, benzyl, phenethyl, phenoxy, phenylthio, phenoxymethyl, phenoxyethyl, phenylthiomethyl, phenylthioethyl, benzyloxy or benzylthio, each of which is optionally mono- or di-substituted in the phenyl part by identical or different substituents, possible substituents being the substituents on phenyl which have already been mentioned for R.
A preferred object of the present invention are antimycotic compositions containing nikkomycin derivatives and azole antimycotics more specifically described in GB-PS 1,351,542, CA-PS 225,504, CA-AS 946,391, AU-PS 542,110, AU-PS 551,411, US-PS 4,301,166, US-PS 4,381,306, US-PS 4,246,274, US-PS 4,238,498, US-PS 4,207,328, US-PS 3,986,229 and DE-OS 3,242,249 which are incorporated into this patent application by reference.
Another preferred embodiment of the present invention are antimycotic compositions containing nikkomycin derivatives and azole antimycotics described in the following paragraphs.
a) Diazolylalkyl-carbinols of the general formula ##STR25## in which A represents a nitrogen atom or the CH group,
and physiologically acceptable acid addition salts thereof.
The compounds of the formula (I) sometimes have two asymmetric carbon atoms. In this case, they can exist in two geometric isomer forms.
The substituted diazolylalkyl-carbinols of the formula (I) are obtained by a process in which azolyloxiranes of the formula ##STR27## in which B, R, X and Y have the abovementioned meaning, are reacted with azoles of the formula ##STR28## in which A has the abovementioned meaning, in the presence of a diluent and, if appropriate, in the presence of a base.
Preferably, in formula (I)
A represents a nitrogen atom or the CH group,
B represents a nitrogen atom or the CH group,
X represents hydrogen or straight-chain or branched alkyl with 1 to 6 carbon atoms,
Y represents straight-chain or branched alkyl with 1 to 6 carbon atoms; or, if X represents hydrogen, also straight-chain or branched alkenyl or alkinyl with in each case 3 to 6 carbon atoms or benzyl with is optionally mono-, di- or tri-substituted in the phenyl art by identical or different substituents, substituents which may be mentioned being: halogen, alkyl with 1 to 4 carbon atoms, alkoxy and alkylthio with in each case 1 to 4 carbon atoms, halogenoalkyl, halogenoalkoxy and halogenoalkylthio with in each case 1 or 2 carbon atoms and 1 to 5 identical or different halogen atoms, such as, preferably, fluorine and chlorine atoms, nitro- and cyano; and
R represents phenyl which is optionally mono-, di- or tri-substituted by identical or different substituents, preferred substituents which may be mentioned being: halogen, alkyl with 1 to 4 carbon atoms, alkoxy and alkylthio with in each case 1 to 4 carbon atoms, halogenoalkyl, halogenoalkoxy and halogenoalkylthio with in each case 1 or 2 carbon atoms and 1 to 5 identical or different halogen atoms, such as, preferably, fluorine and chlorine atoms, nitro, cyano, hydroxyl, hydroxycarbonyl, alkoxycarbonyl with 1 to 4 carbon atoms in the alkyl part, hydroximinoalkyl with 1 to 4 carbon atoms, alkoximinoalkyl with 1 to 4 carbon atoms in each alkyl part and phenyl, phenoxy, benzyl and benzyloxy, each of which is optionally substituted by halogen and/or alkyl with 1 or 2 carbon atoms; or
R preferably represents the grouping ##STR29## wherein Alk.sup.1 represents straight-chain or branched alkyl with 1 to 4 carbon atoms; and
Particularly preferred compounds of the formula (I) are those in which
A represents a nitrogen atom or the CH group,
B represents a nitrogen atom or the CH group,
X represents hydrogen or straight-chain or branched alkyl with 1 to 4 carbon atoms,
Y represents straight-chain or branched alkyl with 1 to 4 carbon atoms; or, if X represents hydrogen, also allyl, methallyl, propargyl, methylpropargyl or benzyl which is optionally mono- or di-substituted in the phenyl part by identical or different substituents, substituents which may be mentioned being: fluorine, chlorine, bromine, methyl, isopropyl, tert.-butyl, methoxy, methylthio, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, nitro and cyano;
R represents phenyl which is optionally mono- or di-substituted by identical or different substituents, substituents which may be mentioned being: fluorine, chlorine, bromine, methyl, isopropyl, tert.-butyl, methoxy, methylthio, trifluoromethyl, trifluoromethoxy, hydroxycarbonyl, methoxycarbonyl, ethoxycarbonyl, hydroximinomethyl, 1-hydroximinoethyl, methoximinomethyl, 1-methoximinoethyl and phenyl, phenoxy, benzyl and benzyloxy, each of which is optionally substituted by fluorine, chlorine or methyl; or
R represents the grouping ##STR30## wherein Alk.sup.1 represents methyl or ethyl; and
Addition products of acids and those substituted diazolylalkyl-carbinols of the formula (I) in which the substituents A, B, X, Y and R have the meanings which have already been mentioned as preferred for these substituents are also preferred compounds according to the invention.
Preferred acids which can be added on azoles mentioned under a), b), c), d) and e) include hydrogen halide acids, such as, for example, hydrochloric acid and hydrobromic acid, in particular hydrochloric acid, and furthermore phosphoric acid, nitric acid, monofunctional and bifunctional carboxylic acids and hydroxycarboxylic acids, such as, for example acetic acid, maleic acid, succinic acid, fumaric acid, tartaric acid, citric acid, salicyclic acid, sorbic acid and lactic acid, and sulphonic acids, such as o-toluenesulphonic acid and 1,5-naphthalenedisulphonic acid.
b) Substituted 1,3-diazolyl-2-propanols of the general formula ##STR31## in which Alk.sup.1 represents straight-chain or branched alkyl and
and physiologically acceptable acid addition salts thereof.
The substituted 1,3-diazolyl-2-propanols of the formula (I') are obtained by a process in which 2-azolylmethyl-oxiranes of the formula ##STR32## in which Alk.sup.1, Alk.sup.2, R and X have the abovementioned meaning, are reacted with azoles of the formula ##STR33## in which Y has the abovementioned meaning, in the presence of a diluent and, if appropriate, in the presence of a base.
If appropriate, an acid can then be added onto the compounds of the formula (I') thus obtained.
Moreover, the compounds of the general formula (I') in which R represents in each case optionally substituted phenylthio, phenylthioalkyl or benzylithio can be oxidised to the corresponding SO or SO.sub.2 derivatives in the customary manner.
Formula (I') provides a general definition of substituted 1,3-diazolyl-2-propanols according to this section b) of the invention. Preferably, in this formula,
Particularly preferred compounds of the formula (I') are those in which
Addition products of acids and those substituted 1,3-diazolyl-2-propanols of the formula (I') in which the substituents Alk.sup.1, Alk.sup.2, X, Y and R have the meanings which have already been mentioned as preferred for these substituents are also preferred compounds according to the invention.
c) Substituted azolylcyclopropyl-azolylmethyl-carbinol derivatives of the formula (I") ##STR34## in which Ar represents optionally substituted aryl or optionally substituted heteroaryl,
and their acid addition salts have good anitimicrobial, in particular antimycotic, properties when used according to this invention.
The substituted azolylcyclopropyl-azolylmethylcarbinol derivatives of the formula (I") which are to be used according to the invention show a good spectrum of action in certain areas of indication.
The substituted azolylcyclopropyl-azolylmethylcarbinol derivatives are generally defined by formula (I"). In this formula,
Particularly preferred compounds of the formula (I") are those in which
Preferred compounds according to this section of the invention are also addition products of acids and those substituted azolylcyclopropyl-azolylmethylcarbinol derivatives of the formula (I") in which Ar, R, X and Y have the meanings which have already been mentioned as preferred for these radicals.
d) substituted azolylmethyl-cyclopropyl-carbinol derivatives of the formula (I"') ##STR35## in which Ar represents optionally substituted aryl or optionally substituted heteroaryl,
The substituted azolylmethyl-cyclopropyl-carbinol derivatives of the formula (I"') which are to be used according to this section of invention show a good spectrum of action in certain areas of indication.
The substituted azolylmethyl-cyclopropyl-carbinol derivatives according to the invention are generally defined by formula (I"'). In this formula,
wherein
Particularly preferred compounds of the formula (I"') are those in which
wherein
other preferred compounds according to the invention are addition products of acids and those substituted azolylmethyl-cyclopropyl-carbinol derivatives of the formula (I"') in which Ar, R.sup.1, R.sup.2 and Y have the meanings which have already been mentioned as being preferred for these radicals.
The substituted azolylmethyl-cyclopropyl-carbinol derivatives which are to be used according to this section of the invention and their acid addition salts have not yet been described. They can be obtained in a generally known manner.
e) Hydroxyethyl-azole derivatives of the general formula ##STR39## in which R.sup.1 represents alkyl or the grouping Ar-Y-,
and acid addition salts thereof, have good antimycotic properties for the purpose of the present invention.
The compounds of the formula (I"") have an asymmetric carbon atom and can therefore be obtained in the two optical isomer forms.
The hydroxyethyl-azole derivatives of the formula (I"") to be used according to this section of the invention have a good action spectrum in certain fields of indication.
Formula (I"") provides a general definition of the hydroxyethyl-azole derivatives according to the invention. Preferably, in this formula
R.sup.1 represents straight-chain or branched alkyl with 1 to 6 carbon atoms or the grouping Ar-Y;
Ar represents naphthyl, or phenyl which is optionally monosubstituted or polysubstituted by identical or different substituents, preferred substituents which may be mentioned being: halogen, alkyl with 1 to 4 carbon atoms, alkoxy and alkylthio with in each case 1 or 2 carbon atoms, nitro, halogenoalkyl, halogenoalkoxy and halogenoalkylthio with in each case 1 or 2 carbon atoms and 1 to 5 identical or different halogen atoms, such as, preferably, fluorine and chlorine atoms, the --CH.dbd.NOR.sup.2 radical, and phenyl, phenoxy, benzyl and benzyloxy, each of which is optionally substituted by halogen and/or alkyl with 1 or 2 carbon atoms;
X represents a nitrogen atom or the CH group;
Y represents a direct bond or the groupings --CH.sub.2 --, --CH.sub.2 CH.sub.2 --, --OCH.sub.2 --, --SCH.sub.2 --, --CH.dbd.CH-- or --C.tbd.C--;
Z represents oxygen or the NOR.sup.2 group; and
R.sup.2 represents hydrogen, straight-chain or branched alkyl with 1 to 6 carbon atoms, alkenyl or alkinyl with in each case 2 to 6 carbon atoms, or phenylalkyl which has 1 or 2 carbon atoms in the alkyl part and is optionally monosubstituted or polysubstituted by identical or different substituents, possible substituents on the phenyl being the substituents on phenyl which have already been mentioned in the case of Ar; or represents cycloalkylmethyl which has 5 or 6 carbon atoms in the cycloalkyl part and is optionally mono-, di-or trisubstituted by identical or different alkyl radicals with 1 to 3 carbon atoms.
Particularly preferred compounds of the formula (I"") are those in which
R.sup.1 represents straight-chain alkyl with 1 to 6 carbon atoms or the grouping Ar-Y-;
Ar represents naphthyl, or represents phenyl which is optionally mono-, di- or trisubstituted by identical or different substituents, substituents which may be mentioned being: fluorine, chlorine, methyl, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, methoximinomethyl, ethoximinomethyl and allyloximinomethyl, and phenyl, phenoxy, benzyl and benzyloxy, each of which is optionally substituted by chlorine and/or methyl;
X represents a nitrogen atom or the CH group;
Y represents a direct bond or the groupings --CH.sub.2 --, --CH.sub.2 CH.sub.2 --, --OCH.sub.2 --, --SCH.sub.2 --, --CH.dbd.CH-- or --C.tbd.C--; and
Z represents oxygen or the NOR.sup.2 group,
wherein
R.sup.2 represents hydrogen, methyl, ethyl, n-propyl, n-butyl, allyl or propargyl, or represents benzyl which is optionally mono-, di- or trisubstituted by identical or different substituents from the group comprising fluorine, chlorine, methyl, trifluoromethyl and trifluoromethoxy, or represents cyclohexylmethyl which is optionally substituted by methyl or ethyl.
Another preferred embodiment of the invention are compositions comprising a fungicidally effective amount of a nikkomycin derivative selected from the group consisting of nikkomycins Z.sub.t, X.sub.t, B, Bx, C and Cx (see U.S. Pat. No. 4,585,761, U.S. Pat. No. 4,315,922, U.S. Pat. No. 4,158,608 and U.S. Pat. No. 4,046,881) and an antimycotically active and optionally orally applicable azole.
Moreover, antimycotic compositions are preferred comprising an azole antimycotic selected from the group consisting of ketoconazole, itraconazole, fluconazole, clotrimazole, miconazole, bifonazole, 1-(4-chlorphenyl) -2-methyl-2-methoximo-methyl-1-(1,2,4-triazol-1-yl -methyl)-1-propanol, 1-(4-chlorphenyl)-3,3-dimethyl-2-(1,2,4-triazol-1-yl-methyl)-2-butanol and 4-(fluorphenyl) -(1-methylsulfinyl-1-cyclopropyl)-(1,2,4-triazol -1-yl-methyl)-methanol.
The antimycotic compositions according to the invention contain a fungicidally effective amount of a nikkomycin derivative and an azole antimycotic in a ratio of 1:1 to 30:1, preferably 3:1 to 10:1.
Preferred are also antimycotic compositions according to the invention comprising a fungicidally effective amount of a nikkomycin derivative and an azole antimycotic selected from the group consisting of ketoconazole, itraconazole, fluconazole, clotrimazole, miconazole, bifonazole, 1-(4-chlorphenyl)-2-methyl-2-methoximo-methyl-1-(1,2,4-triazol-1-yl-methyl -1-propanol, 1-(4-chlorphenyl)-3,3-dimethyl-2-(1,2,4-triazol-1-yl-methyl)-2-butanol and 4-(fluorphenyl)-(1-methylsulfinyl-1-cyclopropyl)-(1,2,4-triazol-1-yl -methyl)-methanol and, moreover, the antimycotic compositions comprising a fungicidally effective amount of nikkomycin Z and 1(4-chlorphenyl)-2-methyl-2-methoximomethyl 1-(1,2,3-triazol-1-yl-methyl-1-propanol, 1-(4-chlorphenyl)-3,3-dimethyl-2-(1,2,4-triazol-1-yl-methyl) -2-butanol and/or 4-(fluorphenyl)-(1-methylsulfinyl-1-cyclopropyl)-(1,2,4-triazol-1-yl-methy l)-methanol.
A further embodiment of the invention are nikkomycins in combination with antimycotically active and optionally orally applicable azoles for use in a method for therapeutical treatment of the human or animal body infected with fungi.
The invention is also related to the use of nikkomycin derivatives in combination with antimycotically active and optionally orally applicable azoles for the preparation of antimycotically active pharmaceutical compositions and to a process for the preparation of antimycotically active pharmaceutical compositions comprising mixing a combination of a fungicidally effective amount of a nikkomycin derivative and an azole derivative with a solid or liquid diluent and/or carrier or other auxiliaries useful for the preparation of pharmaceutical compositions, said nikkomycin derivative and azole derivative preferably being present in a ratio of 1:1 to 30:1.
Finally, the invention is also related to a method of treating human or non-human animals infected with fungi, the method comprising administering to the human or non-human animal therapeutically effective amounts of a nikkomycin derivative and an azole antimycotic.
More specifically the invention is related to a method comprising administering to the human or non-human animal of from 1 mg/kg to 1,000 mg/kg, preferably 10 mg/kg to 100 mg/kg of body weight per day of a nikkomycin derivative and an azole antimycotic of the above identified type. The method comprising administering the nikkomycin and the azole in a ratio of 1:1 to 30:1 is also preferred.
Preferably the compositions according to the invention are orally administered, but may be administered parenterally or via the inhalation of an aerosilized preparation.